A study of the renin-angiotensin-aldosterone system in severe infantile malnutrition

Renin activity, renin substrate and aldosterone were measured in plasma of 17 children aged 12 to 28 months and suffering from severe malnutrition (marasmic kwashiorkor). Plasma renin activity was very high (median 29.0 ng/ml/hr) at admission, decreased after equilibration with a normal sodium diet (9.9 ng/ml/hr) and was negatively correlated with urinary sodium excretion. Plasma renin substrate and aldosterone concentrations were in the normal range; plasma aldosterone correlated positively with serum potassium. The hyperactivity of the renin-angiotensin system may be of relevance to the renal function in severe malnutrition.     

Renal tubular acidosis type 4 in neonatal unilateral kidney diseases

Three neonates, two with unilateral renal vein thrombosis and one with unilateral dysplastic kidney, developed type 4 renal tubular acidosis, manifested by nonazotemic hyperkalemic metabolic acidosis with alkaline urine pH and reduced potassium excretion. Normal plasma concentrations of sodium, aldosterone, and renin activity, together with normal renal fractional excretion of sodium, supported the diagnosis of renal tubular acidosis type 4, subtype 5. Arginine HCl loading studies showed that despite their ability to bring the urine pH to less than 5.8, net acid excretion was inadequate relative to the corresponding plasma bicarbonate concentration. Treatment with oral bicarbonate resulted in sustained normalization of blood acid-base status and accelerated linear growth in the first two infants, in whom spontaneous recovery occurred by ages 8 and 15 months, respectively. At that time, the affected kidneys were extremely small with distorted collecting systems; the contralateral kidneys showed compensatory hypertrophy. In the third infant, persistent acidosis and growth failure resulted from medical noncompliance; the removal of the dysplastic kidney at 7 months of age was followed by the return to normal blood acid-base status and normalized tubular hydrogen and potassium excretion. We conclude that neonatal unilateral kidney disease can result in renal tubular subtype 5. Spontaneous recovery can be expected, presumably because of " autonephrectomy " of the affected kidney plus the compensatory hypertrophy of the contralateral kidney.     

Type 4 renal tubular acidosis (subtype 2) in a patient with methylmalonic acidaemia

A 10-month-old male infant with vitamin B₁₂ non-responsive methylmalonic acidaemia is reported. Laboratory results revealed hyperkalaemic, hyperchloraemic, metabolic acidosis with slight azotaemia. The urinary pH decreased (below 5.5) to compensate for acidaemia. Levels of plasma renin activity and plasma aldosterone concentration were low. The renal biopsy showed tubulo-interstitial nephritis. We suggested the diagnosis of type 4 renal tubular acidosis, subtype 2, i.e. hyporeninaemic hypoaldosteronism. We suggest that chronic renal disease may be a common complication of methylmalonic acidaemia.     

Effects of ADH on the activity and function of the renin-angiotensin-aldosterone system in infants and in children

In babies ranging in age from 1 to 25 weeks and in children between 1 and 14 years, plasma renin activity and urinary aldosterone activity were determined in relation to urinary sodium excretion. A reciprocal correlation was found demonstrating that the hyperactivity of the renin-angiotensin-aldosterone system is stimulated in infants by a low sodium intake. A second stimulus was observed in the influence of the hypothalamo-neurohypophyseal system, when the plasma renin activity was suppressed by administration of antidiuretic hormone and sodium excretion increased due to a decreased aldosterone activity.Our study suggests that there exists a feedback between the renin-angiotensin-aldosterone system and ADH release and that this feedback plays an important role in the regulation of water and electrolyte balance in the young infant.Supported by Deutsche Forschungsgemeinschaft.     

The effect of metoclopramide administration on electrolyte status and activity of renin-angiotensin-aldosterone system in premature infants

The present study has been carried out to define whether endogenous dopamine contributes to the regulation of renal sodium handling and the function of the renin-angiotensin-aldosterone system in low birth weight premature infants. Twelve premature infants with mean birth weight of 1420 g and mean gestational age of 29.2 wk were given metoclopramide (MTC) in a dose of 0.1 mg/kg/day to treat delayed gastric emptying, regurgitation, and abdominal distension at the age of 17-23 days. Infants were kept on either a low (2-3 mEq/kg/day) or high (4-7 mEq/kg/day) sodium diet to modulate activity of RAAS. Prior to and after a 3-day period of MTC administration, blood samples were taken, and in six male infants 24-h urine collections were made to determine plasma and urine electrolytes, plasma renin activity, plasma aldosterone concentration, and urinary aldosterone excretion. We demonstrated that plasma sodium and potassium concentrations and plasma renin activity were not altered by MTC. On the other hand, in response to MTC, there was a significant increase in urinary sodium excretion (1.8 +/- 0.3 versus 2.3 +/- 0.3 mEq/kg/day) and a decrease in potassium excretion (1.2 +/- 0.2 versus 0.8 +/- 0.1 mEq/kg/day); plasma aldosterone concentration and urinary aldosterone excretion decreased significantly from initial values of 2101 +/- 274 pg/ml and 2.91 +/- 0.52 micrograms/day to 1500 +/- 207 pg/ml (p less than 0.01) and 2.21 +/- 0.43 micrograms/day (p less than 0.01), respectively, after MTC. These alterations were independent of the pretreatment hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium and water homeostasis in children with shigellosis

Studies in Bangladesh have shown that the mortality in shigellosis is significantly higher in hyponatraemic (HN) than in normo- (NN) or hypernatraemic children. The aim of this study was to describe the effect of shigellosis on renal haemodynamics and sodium and water homeostasis before treatment was started. Twenty-one moderately ill children infected with Shigella dysenteriae type 1 were studied. Eight of them had a serum sodium concentration below 130 mmol/L. Renal function was determined by glomerular filtration rate measured by clearances of inulin and iohexol. Effective renal plasma flow was estimated by clearance of paraaminohippuric acid. Plasma renin, aldosterone and anti-diuretic hormone were also studied. The HN children had significantly higher haemoglobin and haematocrit levels than the NN group. There was an inverse correlation between serum sodium and haemoglobin, and a direct correlation between serum sodium and urinary sodium and urinary chloride. Direct correlations were found between serum aldosterone and haemoglobin, plasma renin and systolic blood pressure and an inverse correlation between serum aldosterone and serum sodium. Clearances of inulin and iohexol were normal. Detectable levels of ADH were found in both groups, despite low serum osmolalities.

Conclusion : The HN state seems to be triggered by multiple factors. The normal glomerular filtration rate excludes a volume expansion secondary to reduced renal function. Inappropriate or a physiological increase of anti-diuretic hormone secretion may be of importance. The higher sodium losses in stools of the HN children might also be a factor contributing to the HN.     

Pseudo-hypo aldosteronism Type II

A 50-day-old infant diagnosed as meningitis had persistently elevated serum potassium, low serum bicarbonate and normal serum sodium. She had metabolic acidosis with low TTKG, low serum renin and low normal serum aldosterone with no renal failure or extra renal causes of hyperkalemia. Hence a diagnosis of Type II pseudo-hypoaldosteronism was made. She was started on oral thiazide following which her serum electrolytes normalized.     

Early Childhood Hyperkalemia: Variety of Pseudohypoaldosteronism

ABSTRACT. Fractional excretion of electrolytes, renal acidification capacity and the renin-aldosterone system have been studied in 5 non-azotemic children, 19-25 months old, with mineralo-corticoid resistant hyperkalemia, discovered in the first month of life. Although fractional potassium excretion was similar in patients and in a group of control healthy children (13.8± 5.2% vs. 8.7±6.4%) it was inappropriately low in the patients for their higher potassium concentration. Fractional sodium excretion was significantly increased in the patients (1.6±0.3% vs. 0.67±u.4, p<0.02). Normal net acid and ammonium excretion and intact ability to lower urinary pH during acid loading were observed in all patients. Mean values for plasma aldosterone (37.0±9.1 vs. 13.9±11.2 ng/dl), plasma renin activity (12.5±3.9 vs. 8±2.8 ng/ml/h) and plasma aldosterone/plasma potassium ratio (7.11±1.5 vs. 3.08 ±1.7) were higher in the patients than in the control subjects (all p<0.001). These data support the hypothesis that a partial lack of response of the renal tubule to endogenous mineralocorticoids was present in the patients. This type of pseudohypoaldosteronism is less severe than that described for the classic form and for early childhood renal acidosis.     

Early childhood hyperkalemia: variety of pseudohypoaldosteronism

Fractional excretion of electrolytes, renal acidification capacity and the renin-aldosterone system have been studied in 5 non-azotemic children, 19-25 months old, with mineralocorticoid resistant hyperkalemia, discovered in the first month of life. Although fractional potassium excretion was similar in patients and in a group of control healthy children (13.8 +/- 5.2% vs. 8.7 +/- 6.4%) it was inappropriately low in the patients for their higher potassium concentration. Fractional sodium excretion was significantly increased in the patients (1.6 +/- 0.3% vs. 0.67 +/- 0.4, p less than 0.02). Normal net acid and ammonium excretion and intact ability to lower urinary pH during acid loading were observed in all patients. Mean values for plasma aldosterone (37.0 +/- 9.1 vs. 13.9 +/- 11.2 ng/dl), plasma renin activity (12.5 +/- 3.9 vs. 8 +/- 2.8 ng/ml/h) and plasma aldosterone/plasma potassium ratio (7.11 +/- 1.5 vs. 3.08 +/- 1.7) were higher in the patients than in the control subjects (all p less than 0.001). These data support the hypothesis that a partial lack of response of the renal tubule to endogenous mineralocorticoids was present in the patients. This type of pseudohypoaldosteronism is less severe than that described for the classic form and for early childhood renal acidosis.     

Hyperchloremic metabolic acidosis as a clue to recto-urethral fistula in an infant with anal atresia

An infant with high anal atresia and transverse colostomy, in whom initial radiologic evaluation of the urinary tract had been normal, developed hyperchloremic metabolic acidosis at 24 days of age. Gastroenteritis and renal tubular acidosis as possible causes for this metabolic disturbance were excluded, which prompted a repeat investigation of the possibility of a communication between the urinary tract and the rectum. A recto-urethral fistula was demonstrated by urethrography. Analysis of the fluid obtained from the left colon as compared to urine in the bladder and voided urine demonstrated that electrolyte exchange was taking place in the colon, resulting in hyperchloremic hypokalemic acidosis. Treatment with oral sodium bicarbonate and daily lavage of the left colon resulted in normalization of the acid-base status and catch-up growth of the baby. Hyperchloremic acidosis associated with anal atresia and recto-urinary communication appears to be uncommon. However, early diagnosis and treatment of the metabolic derangement are of importance as it may determine the infant's overall prognosis.     

Ammonium chloride metabolic acidosis and the activity of renin-angiotensin-aldosterone system in children

The present study was undertaken to assess the effects of acute metabolic acidosis on the activity of the renin-angiotensin-aldosterone system in 12 children with a mean age of 8.9 years who underwent NH₄Cl loading test. Ammonium chloride was given in a dose of 0.15 g/kg per day for 3 consecutive days to evaluate renal acidification. Prior to and following NH₄Cl administration blood acid-base parameters, plasma and urine electrolytes, creatinine and aldosterone concentrations as well as plasma renin activity (PRA), urine flow rate and net H⁺ excretion were measured. Ammonium chloride administration significantly depressed blood pH (P<0.05), bicarbonate (P<0.01) and base excess (P<0.01) and resulted in a slight, but significant elevation of plasma potassium concentration (P<0.05). Furthermore, NH₄Cl ingestion induced a marked increase in urine flow rate (P<0.01) and urinary sodium, potassium and chloride excretion (P<0.01). In response to NH₄Cl metabolic acidosis, PRA doubled (4.72±1.18 vs 8.13±1.02 ng/ml per hour,P0.05) and there was a nearly fourfold increase in plasma aldosterone level (0.49±0.12 vs 1.52±0.24 ng/ml,P<0.01) and in urinary aldosterone excretion (19.2±4.3 vs 71.8±13.8 g/day,P<0.01). The elevated aldosterone production observed in this study is assumed to be mediated by the combined effect of sodium and water diuresis-related increased PRA, hyperkalaemia and the direct stimulation of adrenal steroidogenesis by metabolic acidosis.     

Secondary pseudohypoaldosteronism caused by urinary tract infection associated with urinary tract anomalies: case reports

Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules and is characterized by renal sodium loss, hyponatremia, hyperkalemia and high plasma aldosterone levels. Although many reasons are described, urinary tract infections and/or urinary tract anomalies are the most common causes. Although the cause of the tubular resistance is not known exactly, renal scar development due to obstruction and reduced sensitivity of mineralocorticoid receptors due to cytokines such as transforming growth factor (TGF)-beta are the possible mechanisms. It is seen especially within the first three months of life and the frequency decreases with age. The treatment is usually elimination of the underlying cause. In this article, we present four patients with several urinary tract anomalies and concomitant urinary tract infection who developed transient secondary pseudohypoaldosteronism.     

Hyperkalemic distal renal tubular acidosis in salt-losing congenital adrenal hyperplasia

Functional indices of distal urinary acidification were assessed in two male infants, aged 1 and 3 months, with salt-losing congenital adrenal hyperplasia. In both cases the diagnosis was sustained by the presence of elevated plasma levels of 17-hydroxyprogesterone, hyponatremia, hyperkalemia, metabolic acidosis and increased plasma renin activity. Both patients were unable to lower urinary pH below 5.9 either during acute ammonium chloride-induced acidosis or after i.v. administration of furosemide. One patient also failed to decrease urine pH below 5.5 and to increase urinary potassium excretion during sodium sulfate infusion. Oral sodium bicarbonate loading was given to both patients but failed to induce a significant increase in the urine minus blood PCO2 gradient. This gradient remained low also after neutral phosphate administration. Repeated studies after acute administration of fludrocortisone in one case or after prolonged administration of hydrocortisone in the other resulted in complete normalization of all functional studies. We conclude that salt-losing congenital adrenal hyperplasia can lead to hyperkalemic distal renal tubular acidosis in early infancy. The defective renal secretion of hydrogen ion and potassium is probably related to the abolishment of the negative potential difference in the cortical collecting tubule induced by the impaired reabsorption of sodium.     

Hyponatraemic hypertensive syndrome in two extremely low birthweight infants

Two cases of hyponatraemic hypertensive syndrome occurring in extremely low birthweight infants are presented. Both infants experienced unilateral renal ischaemia resulting in hyponatraemia and hypertension. A proposed pathophysiological mechanism, namely unilateral renal ischaemia leading to a pressure-natriuresis in the contralateral kidney, is presented. This is associated with an increase in plasma renin and aldosterone, with a paradoxical increase in urinary sodium loss. Immature renal tubular function and relative aldosterone resistance could place the extremely low birthweight infant at increased risk for the condition. The paucity of reports suggests that the condition might be under-recognized.     

Hyperkalemic Distal Renal Tubular Acidosis in Salt-Losing Congenital Adrenal Hyperplasia

ABSTRACT. Functional indices of distal urinary acidification were assessed in two male infants, aged 1 and 3 months, with salt-losing congenital adrenal hyperplasia. In both cases the diagnosis was sustained by the presence of elevated plasma levels of 17-hydroxyprogesterone, hyponatremia, hyperkalemia, metabolic acidosis and increased plasma renin activity. Both patients were unable to lower urinary pH below 5.9 either during acute ammonium chloride-induced acidosis or after i.v. administration of furosemide. One patient also failed to decrease urine pH below 5.5 and to increase urinary potassium excretion during sodium sulfate infusion. Oral sodium bicarbonate loading was given to both patients but failed to induce a significant increase in the urine minus blood P_co2 gradient. This gradient remained low also after neutral phosphate administration. Repeated studies after acute administration of fludrocortisone in one case or after prolonged administration of hydrocortisone in the other resulted in complete normalization of all functional studies. We conclude that salt-losing congenital adrenal hyperplasia can lead to hyperkalemic distal renal tubular acidosis in early infancy. The defective renal secretion of hydrogen ion and potassium is probably related to the abolishment of the negative potential difference in the cortical collecting tubule induced by the impaired reabsorption of sodium.     

Renal hemodynamics and functional changes during the transition from fetal to newborn life in sheep

The effects of delivery on renal function and renal hemodynamics were studied in conscious and chronically instrumented fetal sheep. Each fetus was studied 1 h before delivery and 1, 4, and 24 h following delivery by cesarean section. Delivery was not associated with significant changes in plasma renin activity, plasma angiotensin II, plasma aldosterone, and plasma arginine vasopressin concentrations when determined 1 h after birth. On the other hand, the transition from fetal to newborn life was accompanied by significant increases in plasma epinephrine and norepinephrine concentrations. No significant changes in renal blood flow velocity or in renal vascular resistance were observed during the transition from fetal to newborn life; percent changes in renal blood flow velocity and renal vascular resistance values were respectively 15.4 +/- 11 and -2.4 +/- 1.0% at 1 h, 4.0 +/- 8.0 and 5.8 +/- 9.1% at 4 h, and 3.2 +/- 8.0 and 9.7 +/- 13% at 24 h. No significant changes in urinary flow rate, urine osmolality, free water clearance, and osmolar clearance were observed in the first 24 h following delivery. On the other hand, glomerular filtration rate increased 3-fold from 3.3 +/- 0.4 ml/min in fetuses to 10.1 +/- 1.2 ml/min in newborn lambs at 24 h of age. This rise in glomerular filtration rate was associated with significant decreases in urinary sodium excretion (UNaV) (from 36 +/- 7 to 13 +/- 3 microEq/min) and fractional excretion of sodium (FENa) (from 7.6 +/- 0.9 to 1.1 +/- 0.3%).(ABSTRACT TRUNCATED AT 250 WORDS)     

The renin-angiotensin-aldosterone system in infancy and childhood in basal conditions and after stimulation

Plasma renin activity (PRA), aldosterone (PA), sodium and potassium concentration were measured in 107 healthy infants and children under basal conditions of normal diet and recumbency. Urinary aldosterone (U_Aldo), sodium and potassium were also measured (n=51). A significant (P<0.001) age-related decrease in PRA (r=-0.67), PA (r=-0.67), and U_Aldo (r=-0.56) was observed, with a striking scatter of values especially in infancy. The renin-angiotensin-aldosterone system (RAAS) was also studied after stimulation by standardised sodium restriction during 4 days, followed by acute postural change (n=40). After salt restriction a rise of PRA and U_Aldo was noted, but a rise in PA could not be demonstrated in children aged 0–6 months. The influence of postural change on the RAAS seems more important in older children. The reported values not only in basal but also in stimulated conditions allow study of the RAAS in diseases such as salt loss and hypertension.Abbreviations PRA plasma renin activity - PA plasma aldosterone - U_Aldo urinary aldosterone - RAAS renin-angiotensin-aldosterone system - U_K urinary potassium - U_Na urinary sodium     

RENAL BICARBONATE REABSORPTION AND HYDROGEN ION EXCRETION IN CHILDREN WITH RECURRENT URINARY TRACT INFECTIONS: The Effect of Fluorohydrocortisone

Abstract. Aperia, A., Berg, U. and Broberger, O. (Department of Paediatrics, Karolinska Institutet, S:t Göran's Children's Hospital, Stockholm, Sweden). Renal bicarbonate reabsorption and hydrogen ion excretion in children with recurrent urinary tract infections. The effect of fluorohydrocortisone. Acta Paediat Scand, 63: 209, 1974.–Delayed renal response to ammonium chloride induced acidosis appears to be the earliest detectable residual dysfunction in recurrent urinary tract infections. Control of renal acidifying mechanisms was' therefore studied in 11 girls with recurrent urinary tract infections, but with normal glomerular filtration rates. The renal response to ammonium chloride induced acidosis was normal in 7 and pathological in 4 children. Bicarbonate infusion studies demonstrated that the pathological response to the ammonium chloride load was due to depression of the renal bicarbonate threshold. When, however, the plasma bicarbonate level exceeded the normal renal threshold, i.e. 24.5 mEq/litre, the reabsorptive capacity for bicarbonate was the same in the patients with pathological and normal ammonium chloride tests. Treatment with tluorohydrocortisone resulted in an increase in bicarbonate reabsorption and hydrogen ion secretion in all patients studied. It is suggested that the low bicarbonate threshold in some patients depends on selective tubular damage in a limited number of nephrons. The enhancement of bicarbonate reabsorption by bicarbonate infusion and by fluorohydrocortisone suggests that in the majority of the nephrons renal acidifying mechanisms are intact. It is also suggested that fluorohydrocortisone acts on renal acidifying mechanism mainly by increasing the availability of sodium for exchange with hydrogen ions.     

Late hyponatremia in premature infants: role of aldosterone and arginine vasopressin

To assess the possible involvement of arginine vasopressin in the pathogenesis of late hyponatremia in preterm infants, serial measurements of sodium balance, fractional sodium excretion, plasma and urine osmolality and sodium concentration, and urinary aldosterone and arginine vasopressin excretion were performed at weekly intervals in nine healthy preterm infants. During the course of late hyponatremia, there was a significant increase in urinary aldosterone and arginine vasopressin excretion, from 0.94 +/- 0.16 to 4.30 +/- 0.76 micrograms/day and from 0.38 +/- 0.08 to 1.19 +/- 0.26 ng/day, respectively, from the first to the fourth to fifth weeks. A significant negative correlation was found between fractional sodium excretion and urinary aldosterone excretion. Aldosterone excretion, however, correlated positively with urinary arginine vasopressin excretion in seven of the nine infants. The parallel increase in urinary aldosterone and arginine vasopressin excretion in salt-losing premature infants may occur in response to the protracted contraction of the extracellular fluid compartment, and may contribute to the restoration of volume in the body fluid compartments and to the development of late hyponatremia.     

Molecular mechanism of edema formation in nephrotic syndrome]

Nephrotic edema are the clinical feature of isolated interstitial expansion. Expanded interstitial compartment compensates sodium accumulation in the extracellular volume due to inappropriate renal sodium retention. Renal sodium retention is brought about by an activation of the molecular structures responsible for the reabsorption of sodium along the cortical collecting duct: amiloride-sensitive epithelial sodium channel at the apical face and sodium pump at the basolateral face of the principal cell. This activation is independent of aldosterone and vasopressin. The asymmetry of expansion between interstitium and plasma compartments is due to impaired Starling forces and increased fluid transfer through the capillary wall. The lack of significant changes in transcapillary oncotic and hydrostatic gradients suggests that increased hydraulic conductivity due to transconformation of endothelial intercellular junctions drives the leakage of fluid into the interstitium and allows to understand the mobility of nephrotic edema. Consistently with the site of renal sodium retention and the activation of the epithelial sodium channel, the association of amiloride and furosemide is efficient to increase urinary sodium excretion, to reverse sodium balance and to remove edema from patients with nephrotic syndrome.